α, α-Disubstituted amino acids bearing a terminal alkene on one of their side chains and their salts (“alkene α, α-disubstituted amino acids”) are useful for making cross-linked macrocyclic peptides. For example, International Application No. PCT/US2004/038403 (“the '403 application”) discloses incorporating into a peptide two α, α-disubstituted amino acids that each contain a side-chain bearing a terminal alkene, and cross-linking the terminal alkene groups to form a cross-linked (“stapled”) macrocyclic peptide. The cross-link can, for example, stabilize a secondary structure (e.g., an α-helix) present in the stapled macrocyclic peptide.
International Application Publication No. WO2008/121767 (“the '767 publication”) discloses using alkene α, α-disubstituted amino acids to form stitched polypeptides (e.g., multiple and tandem crosslinked polypeptides) having secondary structures stabilized by stitching. The '403 application, the '767 publication, and other applications, publications, and patents, disclose that stapled and stitched macrocyclic peptides are useful for treating and preventing various diseases including cancer.
Alkene α, α-disubstituted amino acids are thus important and useful building blocks for forming stitched and stapled polypeptides and their precursors. The use of alkene α, α-disubstituted amino acids, however, has been limited by an inability to provide these important molecules in crystalline form. For example, commercially available preparations of alkene α, α-disubstituted amino acids are typically sold as pre-made solutions. The pre-made solutions limit the amount of α, α-disubstituted amino acid that can be shipped per unit volume, limit the chemical reactions that are available to be run with the alkene α, α-disubstituted amino acids, subject the alkene α, α-disubstituted amino acids to an enhanced degradation rate, and are environmentally unfriendly. Thus, there remains a compelling need for crystalline alkene α, α-disubstituted amino acids and their crystalline salts, and processes for producing and using these crystalline amino acids.
In addition, substituting one or more hydrogen atoms of an alkene α, α-disubstituted amino acid with deuterium or a halogen atom can change one or more of the amino acid's properties. For example dipole moment, hydrophobicity, hydrophilicity, steric bulk, or reactivity of an alkene α, α-disubstituted amino acid can be changed by substituting one or more hydrogen atoms thereon with one or more deuterium or halogen atoms. Thus, there also remains a need for optionally crystalline alkene α, α-disubstituted amino acids and their optionally crystalline salts having one or more hydrogen atoms thereon substituted with deuterium or halogen, and methods of making and using these.